OBJECTIVES:We investigated the correlation between polygenic risk of ischemic stroke (and its subtypes) and cognitive ability in 3 relatively healthy Scottish cohortsthe Lothian Birth Cohort 1936 ...(LBC1936), the Lothian Birth Cohort 1921 (LBC1921), and Generation ScotlandScottish Family Health Study (GS).
METHODS:Polygenic risk scores for ischemic stroke were created in LBC1936 (n = 1005), LBC1921 (n = 517), and GS (n = 6,815) using genome-wide association study summary data from the METASTROKE collaboration. We investigated whether the polygenic risk scores correlate with cognitive ability in the 3 cohorts.
RESULTS:In the largest cohort, GS, polygenic risk of all ischemic stroke, small vessel disease stroke, and large vessel disease stroke, but not cardioembolic stroke, were correlated with both fluid and crystallized cognitive abilities. The highest correlation was between a polygenic risk score for all ischemic stroke and general cognitive ability (r = −0.070, p = 1.95 × 10). Few correlations were identified in LBC1936 and LBC1921, but a meta-analysis of all 3 cohorts supported the correlation between polygenic risk of ischemic stroke and cognitive ability.
CONCLUSIONS:The findings from this study indicate that even in the absence of stroke, being at high polygenic risk of ischemic stroke is associated with lower cognitive ability.
Genome-wide scans of genetic variation can potentially provide detailed information on how modern humans colonized the world but require new methods of analysis. We introduce a statistical approach ...that uses Single Nucleotide Polymorphism (SNP) data to identify sharing of chromosomal segments between populations and uses the pattern of sharing to reconstruct a detailed colonization scenario. We apply our model to the SNP data for the 53 populations of the Human Genome Diversity Project described in Conrad et al. (Nature Genetics 38,1251-60, 2006). Our results are consistent with the consensus view of a single "Out-of-Africa" bottleneck and serial dilution of diversity during global colonization, including a prominent East Asian bottleneck. They also suggest novel details including: (1) the most northerly East Asian population in the sample (Yakut) has received a significant genetic contribution from the ancestors of the most northerly European one (Orcadian). (2) Native South Americans have received ancestry from a source closely related to modern North-East Asians (Mongolians and Oroquen) that is distinct from the sources for native North Americans, implying multiple waves of migration into the Americas. A detailed depiction of the peopling of the world is available in animated form.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ankylosing spondylitis (AS) is a common chronic immune-mediated arthropathy affecting primarily the spine and pelvis. The condition is strongly associated with
as well as other human leukocyte ...antigen variants and at least 47 individual non-MHC-associated variants. However, substantial additional heritability remains as yet unexplained. To identify further genetic variants associated with the disease, we undertook an association study of AS in 5,040 patients and 21,133 healthy controls using the Illumina Exomechip microarray. A novel association achieving genome-wide significance was noted at
. Suggestive associations were demonstrated with common variants in
,
and
and with a low-frequency variant in
Two of the variants have been previously associated with inflammatory bowel disease (IBD;
and
). These findings further increase the evidence for the marked similarity of genetic risk factors for IBD and AS, consistent with the two diseases having similar aetiopathogenesis.
To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, ...including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-kB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense. PUBLICATION ABSTRACT
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A recent sperm-typing study by Jeffreys and Neumann suggested that recombination rates in different individuals at the DNA2 recombination hotspot appeared to be highly dependent on their genotype at ...a particular A/G SNP, FG11. Specifically, individuals who carried at least one copy of the A allele at this SNP exhibited rates of crossover considerably higher than those of individuals with no copies. Further, recombinant sperm from heterozygous individuals showed a preferential tendency to carry the G allele. We consider the effects of these phenomena on patterns of linkage disequilibrium and find them to be more subtle than might have been expected. In particular, our analysis suggests that, perhaps surprisingly, patterns of LD among chromosomes carrying the "hot" allele (in this case, A) will typically be similar to those among chromosomes carrying the "cold" allele (G).
Meiotic recombination is a biological process that exchanges the paternal and maternal DNA of chromosomes before they are passed along to offspring. There are two known outcomes of recombination: ...crossover and gene conversion. Recently, finescale human crossover rates have been inferred with some success using population data. However, reliable estimation of gene conversion rates has proven more difficult to come by. We present a new model to jointly estimate crossover and gene conversion rates using an updated version of the PAC Likelihood of Li and Stephens (2003). Furthermore, we incoporate this new model into additional statistical machinery to examine variability in recombination rates across the human genome. We apply our methods to data from the SeattleSNPs project to provide insights into the genome-wide relative rate of gene conversion to crossover in humans, among other features of recombination, under various assumptions.
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